Is ABCA8 p.Met26Ile (c.78G>A) pathogenic?

ABCA8 p.Met26Ile (c.78G>A) is classified Uncertain significance in ABCA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: ambiguous (0.4283); Rare (popmax 0.902%, afr).

How common is ABCA8 p.Met26Ile (c.78G>A) in the general population?

ABCA8 p.Met26Ile (c.78G>A) is rare (popmax 0.902%, afr) (gnomAD).

What do computational predictors say about ABCA8 p.Met26Ile (c.78G>A)?

AlphaMissense predicts ambiguous (score 0.4283) — an in-silico prediction, not a clinical call.

ABCA8 p.Met26Ile

c.78G>A · VCV4089488

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4283 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.902%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4283	ambiguous
REVEL	0.287	benign-leaning
SaProt	LLR -6.97	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.39	GERP -0.44, phastCons 0.67
Regional constraint	o/e 1.01	unconstrained · MANE · 74 kb · p 0.82 · regional, not allelic
Overall
CADD	20.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.902% African / African-American · 676/74,918 alleles

Filtering AF 0.846% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.824%

Overall 0.0453% 729/1,610,564 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.902%	111
Remaining individualsnot grpmax-eligible	0.0497%	2,013
Admixed American	0.0267%	3,747
South Asian	0.0033%	30,297
European (non-Finnish)	0.000255%	392,380

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ABCA8
Protein: p.Met26Ile
Coding: c.78G>A
MANE Select: NM_001288985
Type: single nucleotide variant
Location: chr17:68941957 (GRCh38)
Gene constraint: LOEUF 1.086 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.67

Full ABCA8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCA8 p.Gly176Ser Uncertain significance ★★ ⚠ same type
ABCA8 c.4200-1G>C Benign ★★ same type
ABCA8 p.Gly1225Glu Benign ★★ same type
ABCA8 p.Ile542= Benign/Likely benign ★★ same type
ABCA8 p.Met251Ile Benign ★★ same type
ABCA8 c.3316-8G>T Uncertain significance ★ same type
ABCA8 p.Ala1109Val Uncertain significance ★ ⚠ same type
ABCA8 p.Ala1344Ser Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/abca8-p-met26ile (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown